Biological Regulatory Network Research Articles

Non-coding RNA alterations in occlusal disharmony-induced anxiety-like behaviour.

Occlusal disharmony (OD) may induce anxiety-like behaviours; however, the underlying mechanism remains unclear. Herein, we explored the expression profiles of non-coding RNAs (ncRNAs), along with their biological function and regulatory network, in anxiety-like behaviour induced by OD. Occlusal disharmony was produced by anterior crossbite of C57BL/6 mice. Behavioural tests, corticosterone (CORT) and serotonin (5-HT) levels were used to measure anxiety. In addition, RNA sequencing was used to screen all differentially expressed (DE) ncRNAs. Moreover, the RNA-binding proteins interacting with ncRNAs were predicted by the ENCORI database and confirmed using western blots. The significant differences in behavioural tests and CORT suggested the successful induction of anxiety-like behaviour by OD. In OD mice, ncRNAs were significantly dysregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested that the DE ncRNAs were enriched in anxiety-related pathways. CircRNA10039 was upregulated, and PTBP1 was predicted to interact with circRNA10039. In addition, KEGG pathway analysis showed that PTBP1 may be associated with messenger RNA biogenesis and spliceosomes. OD induced by anterior crossbite can lead to the anxiety-like behaviours. During this process, ncRNA also changes. CircRNA10039 and PTBP1 may play a role in OD-induced anxiety-like behaviours.

Biological regulatory network analysis for targeting the mitochondrial calcium uniporter (MCU) mediated calcium (Ca2+) transport in neurodegenerative disorders

AbstractCalcium (Ca2+) has been observed as the most important ion involved in a series of cellular processes and its homeostasis is critical for normal cellular functions. Mitochondrial calcium uniporter (MCU) complex has been recognized as the most important calcium‐specific channel located in the inner mitochondrial membrane and is one of the major players in maintaining the Ca2+ homeostasis by transporting Ca2+ across the mitochondrial membrane. Furthermore, dysregulation of the mitochondrial Ca2+ homeostasis has been orchestrated to neurodegenerative response. This necessitates quantitative evaluation of the MCU‐dependent mROS production and subsequent cellular responses for more specific therapeutic interventions against neurodegenerative disorders. Towards this goal, here we present a biological regulatory network of MCU to dynamically simulate the MCU‐mediated ROS production and its response in neurodegeneration. Previously, ruthenium complex RuRed and its derivatives have been reported to show low nM to high µM potency against MCU to maintain cytosolic Ca2+ (cCa2+) homeostasis by modulating mitochondrial Ca2+ (mCa2+) uptake. Therefore, structural modeling and dynamic simulation of MCU pore‐forming subunit is performed to probe the interaction profiling of previously reported Ru265 and its derivatives compounds with MCU. The current study highlighted MCU as a potential drug target in neurodegenerative disorders. Furthermore, ASP261 and GLU264 amino acid residues in DIME motif of MCU pore‐forming subunits are identified as crucial for modulating the activity of MCU in neurodegenerative disorders.

Modelling and analysis of the complement system signalling pathways: roles of C3, C5a and pro-inflammatory cytokines in SARS-CoV-2 infection.

The complement system is an essential part of innate immunity. It is activated by invading pathogens causing inflammation, opsonization, and lysis via complement anaphylatoxins, complement opsonin's and membrane attack complex (MAC), respectively. However, in SARS-CoV-2 infection overactivation of complement system is causing cytokine storm leading to multiple organs damage. In this study, the René Thomas kinetic logic approach was used for the development of biological regulatory network (BRN) to model SARS-CoV-2 mediated complement system signalling pathways. Betweenness centrality analysis in cytoscape was adopted for the selection of the most biologically plausible states in state graph. Among the model results, in strongly connected components (SCCs) pro-inflammatory cytokines (PICyts) oscillatory behaviour between recurrent generation and downregulation was found as the main feature of SARS-CoV-2 infection. Diversion of trajectories from the SCCs leading toward hyper-inflammatory response was found in agreement with in vivo studies that overactive innate immunity response caused PICyts storm during SARS-CoV-2 infection. The complex of negative regulators FI, CR1 and DAF in the inhibition of complement peptide (C5a) and PICyts was found desirable to increase immune responses. In modelling role of MAC and PICyts in lowering of SARS-CoV-2 titre was found coherent with experimental studies. Intervention in upregulation of C5a and PICyts by C3 was found helpful in back-and-forth variation of signalling pattern linked with the levels of PICyts. Moreover, intervention in upregulation of PICyts by C5a was found productive in downregulation of all activating factors in the normal SCCs. However, the computational model predictions require experimental studies to be validated by exploring the activation role of C3 and C5a which could change levels of PICyts at various phases of SARS-CoV-2 infection.

Maternal body fluid lncRNAs serve as biomarkers to diagnose ventricular septal defect: from amniotic fluid to plasma.

Background: Maternal body fluids contain abundant cell-free fetal RNAs which have the potential to serve as indicators of fetal development and pathophysiological conditions. In this context, this study aimed to explore the potential diagnostic value of maternal circulating long non-coding RNAs (lncRNAs) in ventricular septal defect (VSD). Methods: The potential of lncRNAs as non-invasive prenatal biomarkers for VSD was evaluated using quantitative polymerase chain reaction (qPCR) and receiver operating characteristic (ROC) curve analysis. The biological processes and regulatory network of these lncRNAs were elucidated through bioinformatics analysis. Results: Three lncRNAs (LINC00598, LINC01551, and GATA3-AS1) were found to be consistent in both maternal plasma and amniotic fluid. These lncRNAs exhibited strong diagnostic performance for VSD, with AUC values of 0.852, 0.957, and 0.864, respectively. The bioinformatics analysis revealed the involvement of these lncRNAs in heart morphogenesis, actin cytoskeleton organization, cell cycle regulation, and protein binding through a competitive endogenous RNA (ceRNA) network at the post-transcriptional level. Conclusion: The cell-free lncRNAs present in the amniotic fluid have the potential to be released into the maternal circulation, making them promising candidates for investigating epigenetic regulation in VSD.

Network pharmacology and molecular docking to explore the potential mechanism of urolithin A in combined allergic rhinitis and asthma syndrome.

This research used network pharmacology, molecular docking, in vivo studies, and other techniques to investigate the biological activity and mechanism of action of urolithin A (UA) in treating combined allergic rhinitis and asthma syndrome (CARAS). Urolithin A and potential related targets of allergic rhinitis and asthma were searched from the public databases. Then, bioinformatics analyses were given to protein-protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, molecular docking and molecular dynamic simulation were performed, aiming at predicting the binding of the active compound to the core target. Finally, in vivo experiment was conducted for further validation. A total of 45 common targets of allergic rhinitis and urolithin A and 62 common targets of asthma and urolithin A were identified, among which six common core targets were screened with Cytoscape. Molecular docking indicated that these core targets had good binding activity to urolithin A, which was further confirmed by molecular dynamics simulation. In the CARAS mouse model, urolithin A showed anti-inflammatory properties. The biological activity and regulatory network of UA on CARAS were revealed, and the anti-inflammatory effect of UA was clarified, which could be associated with the equilibrium of the immune system's Th1/Th2 cells.

Investigating the molecular mechanisms of delirium-like neuropsychiatric disorder induced by electromagnetic pulse based on bioinformatics analysis

Electromagnetic pulse (EMP), a unique type of electromagnetic radiation, may induce diverse neuropsychiatric disorders, such as irritability, hyperkinesis, retardation of learning and memory. However, the underlying mechanism of EMP exposure on neuronal injury has not been elucidated. Here, we aimed to delineate the regulatory expression networks based on high-throughput sequencing data to explore the possible molecular mechanisms related to EMP-induced delirium-like neuropsychiatric disorder in rats. It’s shown that EMP exposure induced anxiety, cognitive decline and short-term memory impairment. The expression profiles of the long noncoding RNAs (lncRNAs) and mRNAs, along with their biological function and regulatory network, were explored in rats after EMP exposure. We identified 41 differentially expressed lncRNAs (DELs) and 266 differentially expressed mRNAs (DEMs) between EMP and sham groups. Sixty-one co-expression relationships between 18 DELs and 56 DEMs were mostly associated with synapse- and metabolic-related pathways. We predicted 51 DEL-miRNA pairs and 290 miRNA-mRNA pairs using the miRanda database to constructed a DEL-miRNA-DEM network. LncRNA AABR07042999.1 and mRNA Tph2, Slc6a4, Dbh and Th were upregulated, and the contents of serotonin, dopamine and norepinephrine were increased in both PFC and HIP after EMP exposure. The current study provided a better understanding of the ceRNA network, which might reveal the pathological mechanism and provide more treatment options for the EMP-induced neurobehavioral disorder.

Static Analysis of Dengue Biological Regulatory Network’s

DENGUE is an acute viral illness caused by the RNA virus of the family Flaviviridae and spread by Aedes mosquitoes. Intense dengue is a spreading cause of serious disease and death in some ’Asian and south American’ countries. Pathogenesis is associated with amended functioning of our innate immune system during infection. Toll Like Receptor is influential for the involucre of innate immunity able to cause of Dengue infection disease like pattern receptor recognition. Toll like receptor induces by injuries of a certain severity arbitrate activation of interferons and Fc receptor arbitrate involucre of cytokines. Clearance of Dengue virus is associated with interferons protein however regulatory mechanisms have been adopted against this modified effect. The clearance considers being a steady state known to be characterized low threshold level of DENV. The pathogenic state is characterized by high threshold level of SOCS. SOCS protein is also induced due to the interferon and cytokine amended signaling which can subsequently play its part in the regulation of interferon and cytokine production. Our hypothesis in this research the innate immunity system is associated between the pathogenesis of Dengue virus and the SOCS amended inhibition. We used the static formalism model of the biological regulatory network of Toll-like receptor induced by the pathogenesis of dengue amended signaling pathway. A model verification method used in GINsim was used to deduce the logical parameters for the qualitative modelling. Therefore, a multidisciplinary and translational study, constructed a formal model constraints approach with a static and integrative computational analysis, which may identify new immunopathological mechanisms and biomarkers for differential diagnosis, opening the way for the development of specific therapies that will reduce mortality and induced morbidity by Dengue virus.

Decoding the Role of Epigenetics in Breast Cancer Using Formal Modeling and Machine-Learning Methods

Breast carcinogenesis is known to be instigated by genetic and epigenetic modifications impacting multiple cellular signaling cascades, thus making its prevention and treatments a challenging endeavor. However, epigenetic modification, particularly DNA methylation-mediated silencing of key TSGs, is a hallmark of cancer progression. One such tumor suppressor gene (TSG) RUNX3 (Runt-related transcription factor 3) has been a new insight in breast cancer known to be suppressed due to local promoter hypermethylation mediated by DNA methyltransferase 1 (DNMT1). However, the precise mechanism of epigenetic-influenced silencing of the RUNX3 signaling resulting in cancer invasion and metastasis remains inadequately characterized. In this study, a biological regulatory network (BRN) has been designed to model the dynamics of the DNMT1–RUNX3 network augmented by other regulators such as p21, c-myc, and p53. For this purpose, the René Thomas qualitative modeling was applied to compute the unknown parameters and the subsequent trajectories signified important behaviors of the DNMT1–RUNX3 network (i.e., recovery cycle, homeostasis, and bifurcation state). As a result, the biological system was observed to invade cancer metastasis due to persistent activation of oncogene c-myc accompanied by consistent downregulation of TSG RUNX3. Conversely, homeostasis was achieved in the absence of c-myc and activated TSG RUNX3. Furthermore, DNMT1 was endorsed as a potential epigenetic drug target to be subjected to the implementation of machine-learning techniques for the classification of the active and inactive DNMT1 modulators. The best-performing ML model successfully classified the active and least-active DNMT1 inhibitors exhibiting 97% classification accuracy. Collectively, this study reveals the underlined epigenetic events responsible for RUNX3-implicated breast cancer metastasis along with the classification of DNMT1 modulators that can potentially drive the perception of epigenetic-based tumor therapy.

Investigation on the differentially expressed circular RNAs in myocardium of mice with diabetic cardiomyopathy

Objective: To identify the differentially expressed circular RNA (circRNA) in the myocardium of diabetic cardiomyopathy (DCM) mice, and analyze their possible biological functions and related regulatory network. Methods: C57BL/6 mice, aged 8 weeks, and weighing were 21-27 g. Eight mice were selected as the control group and 15 mice were selected as the experimental group. The diabetic mice model was established by intraperitoneal injection of streptozotocin in the experimental group. One week after injection, the fasting blood glucose level of mice was measured, and 12 diabetic mice were included in the final experimental group. All mice were fed for 12 weeks under the same laboratory conditions. The cardiac structure and function were detected by echocardiography. Diabetic mice with the left ventricular ejection fraction less than 60% and the E/A less than 1.6 were selected as DCM group (n=3). Mice in DCM group and control group were then sacrificed under deep anesthesia. RNA was extracted from myocardial tissue. High-throughput RNA sequencing technology was used to sequence and identify the RNA in the myocardial tissue of DCM group and normal control group, and the difference was analyzed by DeSeq2. The analysis results were verified at the tissue level by RT-qPCR, and the differential circRNA were analyzed by GO and KEGG pathway analysis. The differentially expressed circRNA-microRNA(miRNA) interaction was predicted by the miRNA target gene prediction software. Results: A total of 63 differentially expressed circRNAs were found in the myocardium of DCM mice. The results of RT-qPCR showed that the tissue level expression of 8 differentially expressed circRNAs was consistent with the sequencing results, of which 7 were up-regulated and 1 was down-regulated. KEGG pathway analysis showed that the up-regulated circRNAs was mainly related to AMPK signal pathway and intercellular adhesion junction pathway, and the down-regulated circRNA was mainly related to cardiomyopathy. Go analysis showed that the up-regulated circRNA was mainly related to the binding process of ions, proteins, kinases and other factors in terms of molecular function, and was involved in regulating the intracellular structure, especially the composition of organelles in terms of cell components. The functional analysis of molecular function and cell components showed that the up-regulated circRNA were related to the cell component origin, recruitment and tissue, and thus participated in the regulation of cell biological process. The down regulated circRNA was related to catalytic activity in terms of molecular function, protein kinase binding process, transferase and calmodulin activity, and was closely related to the components of contractile fibers and the composition of myofibrils. These differentially expressed circRNAs were also related to biological processes such as lysine peptide modification, sarcomere composition, myofibril assembly, morphological development of myocardial tissue, myocardial hypertrophy and so on. Conclusions: In this study, we detected the novel differentially expressed circRNAs in the myocardium of DCM mice, and bioinformatics analysis confirmed that these circRNAs are related to oxidative stress, fibrosis and death of cardiomyocytes, and finally participate in the pathophysiological process of DCM.

A Text Mining Protocol for Mining Biological Pathways and Regulatory Networks from Biomedical Literature.

A biological pathway or regulatory network is a collection of molecular regulators which can activate the changes in cellular processes leading to an assembly of new molecules by series of actions among the molecules. There are three important pathways in system biology studies namely signaling pathways, metabolic pathways, and genetic pathways (or) gene regulatory networks. Recently, biological pathway construction from scientific literature is given much attention as the scientific literature contains a rich set of linguistic features to extract biological associations between genes and proteins. These associations can be united to construct biological networks. Here, we present a brief overview about various biological pathways, biomedical text resources/corpora for network construction and state-of-the-art existing methods for network construction followed by our hybridtext mining protocol for extracting pathways and regulatory networks from biomedical literature.

CREB1K292 and HINFPK330 as Putative Common Therapeutic Targets in Alzheimer's and Parkinson's Disease.

Integration of omics data and deciphering the mechanism of a biological regulatory network could be a promising approach to reveal the molecular mechanism involved in the progression of complex diseases, including Alzheimer’s and Parkinson’s. Despite having an overlapping mechanism in the etiology of Alzheimer’s disease (AD) and Parkinson’s disease (PD), the exact mechanism and signaling molecules behind them are still unknown. Further, the acetylation mechanism and histone deacetylase (HDAC) enzymes provide a positive direction toward studying the shared phenomenon between AD and PD pathogenesis. For instance, increased expression of HDACs causes a decrease in protein acetylation status, resulting in decreased cognitive and memory function. Herein, we employed an integrative approach to analyze the transcriptomics data that established a potential relationship between AD and PD. Data preprocessing and analysis of four publicly available microarray datasets revealed 10 HUB proteins, namely, CDC42, CD44, FGFR1, MYO5A, NUMA1, TUBB4B, ARHGEF9, USP5, INPP5D, and NUP93, that may be involved in the shared mechanism of AD and PD pathogenesis. Further, we identified the relationship between the HUB proteins and transcription factors that could be involved in the overlapping mechanism of AD and PD. CREB1 and HINFP were the crucial regulatory transcription factors that were involved in the AD and PD crosstalk. Further, lysine acetylation sites and HDAC enzyme prediction revealed the involvement of 15 and 27 potential lysine residues of CREB1 and HINFP, respectively. Our results highlighted the importance of HDAC1(K292) and HDAC6(K330) association with CREB1 and HINFP, respectively, in the AD and PD crosstalk. However, different datasets with a large number of samples and wet lab experimentation are required to validate and pinpoint the exact role of CREB1 and HINFP in the AD and PD crosstalk. It is also possible that the different datasets may or may not affect the results due to analysis parameters. In conclusion, our study potentially highlighted the crucial proteins, transcription factors, biological pathways, lysine residues, and HDAC enzymes shared between AD and PD at the molecular level. The findings can be used to study molecular studies to identify the possible relationship in the AD–PD crosstalk.

MiR-155-5p predictive role to decelerate foam cell atherosclerosis through CD36, VAV3, and SOCS1 pathway.

MicroRNAs (miRNAs) are noncoding RNA molecules that play a significant role in atherosclerosis pathogenesis through post-transcriptional regulation. In the present work, a bioinformatic analysis using TargetScan and miRdB databases was performed to identify the miRNAs targeting three genes involved in foam cell atherosclerosis (CD36, Vav3, and SOCS1). A total number of three hundred and sixty-seven miRNAs were recognized and only miR-155–5p was selected for further evaluation based on Venn analysis. Another objective of this study was to evaluate the biological process and regulatory network of miR-155–5p associated with foam cell atherosclerosis using DIANA, DAVID, Cytoscape, and STRING tools. Additionally, the comprehensive literature review was performed to prove the miR-155–5p function in foam cell atherosclerosis. miR-155–5p might be related with ox-LDL uptake and endocytosis in macrophage cell by targeting CD36 and Vav3 genes which was showed from the KEGG pathways hsa04979, hsa04666, hsa04145 H, hsa04810, and GO:0099632, GO:0060100, GO:0010743, GO:001745. Furthermore, miR-155–5p was also predicted to increase the cholesterol efflux from macrophage by inhibit SOCS1 expression based on KEGG pathway hsa04120. Eleven original studies were included in the review and strongly suggest the role of miR-155–5p in foam cell atherosclerosis inhibition.

The Roles of Epigenetics Regulation in Bone Metabolism and Osteoporosis.

Osteoporosis is a metabolic disease characterized by decreased bone mineral density and the destruction of bone microstructure, which can lead to increased bone fragility and risk of fracture. In recent years, with the deepening of the research on the pathological mechanism of osteoporosis, the research on epigenetics has made significant progress. Epigenetics refers to changes in gene expression levels that are not caused by changes in gene sequences, mainly including DNA methylation, histone modification, and non-coding RNAs (lncRNA, microRNA, and circRNA). Epigenetics play mainly a post-transcriptional regulatory role and have important functions in the biological signal regulatory network. Studies have shown that epigenetic mechanisms are closely related to osteogenic differentiation, osteogenesis, bone remodeling and other bone metabolism-related processes. Abnormal epigenetic regulation can lead to a series of bone metabolism-related diseases, such as osteoporosis. Considering the important role of epigenetic mechanisms in the regulation of bone metabolism, we mainly review the research progress on epigenetic mechanisms (DNA methylation, histone modification, and non-coding RNAs) in the osteogenic differentiation and the pathogenesis of osteoporosis to provide a new direction for the treatment of bone metabolism-related diseases.

CircRNA hsa_circ_0014130 Function as a miR-132-3p Sponge to Play an Oncogenic Role in Bladder Cancer Cells by Upregulating KCNJ12 Expression

Background: To detect the expression level of hsa_circ_0014130, and explore its biological functions and potential regulatory network in bladder cancer (BCa). Methods: The expression level of hsa_circ_0014130 was detected by qRT-PCR and its relationships to clinicopathological characteristics and prognosis of BCa patients were analyzed. The interactions between hsa_circ_0014130 and microRNA (miRNA) sponge, miRNA and its direct targets, were determined by luciferase reporter gene assay and RNA pull-down assay, and the correlations of their expression were determined by Pearson’s correlation analysis. Findings: hsa_circ_0014130 was markedly overexpressed in BCa samples and related to aggressive characteristics and poor survival. Ectopic expression of hsa_circ_0014130 markedly promoted the cell proliferation, migration, invasion and differentiation of BCa in vitro and tumor xenograft growth in vivo, while malignant biological behaviors were inhibited by hsa_circ_0014130 knockdown. There was an inverse relationship between hsa_circ_0014130 and miR-132-3p expression in BCa tissues and cells. hsa_circ_0014130 function as a competitive endogenous RNA for miR-132-3p to play oncogenic roles in BCa cells. On the other hand, KCNJ12 was a direct target of miR-132-3p at the downstream, and the expression of KCNJ12 was inversely correlated to that of miR-132-3p. Furthermore, a significantly positive correlation between hsa_circ_0014130 and KCNJ12 mRNA expression was found. More importantly, the oncogenic roles of hsa_circ_0014130 overexpression on BCa cells in vitro and in vivo were partially suppressed by ectopic expression of miR-132-3p or KCNJ12 knockdown. These findings suggested that hsa_circ_0014130 exerted its biological roles by regulating miR-132-3p/KCNJ12 expression. Further research revealed hsa_circ_0014130/miR-132-3p/KCNJ12 axis was involved in Epithelial-mesenchymal transition (EMT) process and GSK3β/AKT signaling pathway. Interpretation: hsa_circ_0014130 function as a miR-132-3p sponge to promote the oncogenesis and progression of bladder cancer by regulating KCNJ12 expression. These findings might improve the understanding of tumor pathogenesis and provide novel therapeutic targets for bladder cancer. Funding Information: None. Declaration of Interests: None. Ethics Approval Statement: The written informed consent was signed by each patient in order to notify the applying purpose of her/his tissue sample. All protocols were approved by the Ethics Committee of The Second Hospital of Tianjin Medical University.

Biological Regulatory Network (BRN) Analysis and Molecular Docking Simulations to Probe the Modulation of IP3R Mediated Ca2+ Signaling in Cancer.

Inositol trisphosphate receptor (IP3R) mediated Ca+2 signaling is essential in determining the cell fate by regulating numerous cellular processes, including cell division and cell death. Despite extensive studies about the characterization of IP3R in cancer, the underlying molecular mechanism initiating the cell proliferation and apoptosis remained enigmatic. Moreover, in cancer, the modulation of IP3R in downstream signaling pathways, which control oncogenesis and cancer progression, is not well characterized. Here, we constructed a biological regulatory network (BRN), and describe the remodeling of IP3R mediated Ca2+ signaling as a central key that controls the cellular processes in cancer. Moreover, we summarize how the inhibition of IP3R affects the deregulated cell proliferation and cell death in cancer cells and results in the initiation of pro-survival responses in resistance of cell death in normal cells. Further, we also investigated the role of stereo-specificity of IP3 molecule and its analogs in binding with the IP3 receptor. Molecular docking simulations showed that the hydroxyl group at R6 position along with the phosphate group at R5 position in ‘R’ conformation is more favorable for IP3 interactions. Additionally, Arg-266 and Arg-510 showed π–π and hydrogen bond interactions and Ser-278 forms hydrogen bond interactions with the IP3 binding site. Thus, they are identified as crucial for the binding of antagonists.

Deciphering the expression dynamics of ANGPTL8 associated regulatory network in insulin resistance using formal modelling approaches.

ANGPTL8 is a recently identified novel hormone which regulates both glucose and lipid metabolism. The increase in ANGPTL8 during compensatory insulin resistance has been recently reported to improve glucose tolerance and a part of cytoprotective metabolic circuit. However, the exact signalling entities and dynamics involved in this process have remained elusive. Therefore, the current study was conducted with a specific aim to model the regulation of ANGPTL8 with emphasis on its role in improving glucose tolerance during insulin resistance. The main contribution of this study is the construction of a discrete model (based on kinetic logic of René Thomas) and its equivalent Stochastic Petri Net model of ANGPTL8 associated Biological Regulatory Network (BRN) which can predict its dynamic behaviours. The predicted results of these models are in‐line with the previous experimental observations and provide comprehensive insights into the signalling dynamics of ANGPTL8 associated BRN. The authors’ results support the hypothesis that ANGPTL8 plays an important role in supplementing the insulin signalling pathway during insulin resistance and its loss can aggravate the pathogenic process by quickly leading towards Diabetes Mellitus. The results of this study have potential therapeutic implications for treatment of Diabetes Mellitus and are suggestive of its potential as a glucose‐lowering agent.

A Systematic Analysis Revealed the Potential Gene Regulatory Processes of ATRA-Triggered Neuroblastoma Differentiation and Identified a Novel RA Response Sequence in the NTRK2 Gene.

Retinoic acid- (RA-) triggered neuroblastoma cell lines are widely used cell modules of neuronal differentiation in neurodegenerative disease studies, but the gene regulatory mechanism underlying differentiation is unclear now. In this study, system biological analysis was performed on public microarray data from three neuroblastoma cell lines (SK-N-SH, SH-SY5Y-A, and SH-SY5Y-E) to explore the potential molecular processes of all-trans retinoic acid- (ATRA-) triggered differentiation. RT-qPCR, functional genomics analysis, western blotting, chromatin immunoprecipitation (ChIP), and homologous sequence analysis were further performed to validate the gene regulation processes and identify the RA response element in a specific gene. The potential disturbed biological pathways (111 functional GO terms in 14 interactive functional groups) and gene regulatory network (10 regulators and 71 regulated genes) in neuroblastoma differentiation were obtained. 15 of the 71 regulated genes are neuronal projection-related. Among them, NTRK2 is the only one that was dramatically upregulated in the RT-qPCR test that we performed on ATRA-treated SH-SY5Y-A cells. We further found that the overexpression of the NTRK2 gene can trigger differentiation-like changes in SH-SY5Y-A cells. Functional genomic analysis and western blotting assay suggested that, in neuroblastoma cells, ATRA may directly regulate the NTRK2 gene by activating the RA receptor (RAR) that binds in its promoter region. A novel RA response DNA element in the NTRK2 gene was then identified by bioinformatics analysis and chromatin immunoprecipitation (ChIP) assay. The novel element is sequence conservation and position variation among different species. Our study systematically provided the potential regulatory information of ATRA-triggered neuroblastoma differentiation, and in the NTRK2 gene, we identified a novel RA response DNA element, which may contribute to the differentiation in a human-specific manner.

The molecular mechanism in secondary wall deposition and programmed cell death of wood formation

Wood formation occurs through continuous steps involving cambium cell proliferation, xylem cell specification and expansion, secondary wall deposition and programmed cell death (PCD). Recently, many key transcription factors/repressors and enzymes involved in secondary wall formation and PCD processes have been identified based on genetics and omics analysis in model plants Arabidopsis and poplar. All these hierarchical transcription factors build the transcriptional regulatory network of secondary wall deposition. These transcription factors not only play important role in regulating the biosynthesis of secondary wall components including lignin, cellulose and xylan, but also activate downstream hydrolytic enzymes and trigger PCD process. To analyze the biological function and regulatory network of these genes, it will provide the theoretical foundation for elucidating the molecular mechanism of wood formation. In this paper, we review the advances of transcriptional regulatory network in secondary wall deposition and enzymatic mechanism in PCD of wood formation.

RNA-Sequencing and Bioinformatics Analysis of Long Noncoding RNAs and mRNAs in the Prefrontal Cortex of Mice Following Repeated Social Defeat Stress.

Background Repeated or continuous chronic psychological stress may induce diverse neuropsychiatric disorders; however, the underlying mechanisms remain unclear. In this study, we explored the expression profiles of long noncoding RNAs (lncRNAs) and mRNAs, along with their biological function and regulatory network, in mice after repeated social defeat (RSD) stress to explore their potential involvement in the development of anxiety-like behaviors. Main Methods RNA-sequencing was used to screen all differentially expressed (DE) lncRNAs and mRNAs between the RSD and control groups. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for confirmation of the RNA-sequencing results. The function of DE lncRNAs was predicted by Gene Ontology (GO) enrichment and pathway analyses of target mRNAs. In addition, the functional regulatory network of the target mRNAs was constructed to reveal potential relationships between lncRNAs and their target genes with bioinformatics approaches. Key Findings In mice experiencing RSD, 373 and 454 lncRNAs, along with 1142 and 654, mRNAs were significantly upregulated and downregulated, respectively. The detailed regulatory network included 126 eligible lncRNA-mRNA pairs. Among them, 14 genes such as Arhgef1, Chchd2, Fam107a, Dlg1, Nova2, Dpf1, and Shank3 involved in neurite growth, neural development, and synaptic plasticity were direct targets of the DE lncRNAs. qRT-PCR of four of the DE lncRNAs and mRNAs confirmed the reliability of RNA-sequencing. GO clustering analyses showed that the top enriched biological process, cellular component, and molecular function terms were synaptic transmission, neuron spine, and glutamate receptor binding, respectively. Further, the top three significant enriched pathways were synaptic adhesion-like molecule (SALM) protein interactions at the synapses, trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as glutamate binding, activation of AMPA receptors, and synaptic plasticity. Significance Hundreds of lncRNAs and mRNAs are dysregulated after RSD, and many of these lncRNAs might participate in the development of anxiety-like behaviors via multiple complex mechanisms such as target regulation. Available informatics evidence highlighted the likely role of synapse dysfunction and abnormal synaptic neurotransmission in these behaviors. Thus, our findings provide potential candidate biomarkers or intervention targets for chronic psychological stress-induced neuropsychiatric disorders.

Analysis of Boolean functions based on interaction graphs and their influence in system biology

Biological regulatory network can be modeled through a set of Boolean functions. These set of functions enable graph representation of the network structure, and hence, the dynamics of the network can be seen easily. In this article, the regulations of such network have been explored in terms of interaction graph. With the help of Boolean function decomposition, this work presents an approach for construction of interaction graphs. This decomposition technique is also used to reduce the network state space of the cell cycle network of fission yeast for finding the singleton attractors. Some special classes of Boolean functions with respect to the interaction graphs have been discussed. A unique recursive procedure is devised which uses the Cartesian product of sets starting from the set of one-variable Boolean function. Interaction graphs generated with these Boolean functions have only positive/negative edges, and the corresponding state spaces have periodic attractors with length one/two.